Cationic lipid

Patent metadata

Field	Value
Publication number	US-2017224619-A1
Application number	US-201515322271-A
Country	US
Kind code	A1
Filing date	Jun 30, 2015
Priority date	Jun 30, 2014
Publication date	Aug 10, 2017
Grant date	—

Abstract

The present invention provides a cationic lipid represented by the formula (I)

wherein R 1 and R 2 each represents alkyl having 8 to 24 carbon atoms or the like; R 3 represents a hydrogen atom, alkyl having 1 to 3 carbon atoms, the formula (A)

wherein R 4 and R 5 each represents a hydrogen atom or the like, and n 3 represents an integer from 2 to 6, or the formula (B)

wherein R 6 and R 7 each represents a hydrogen atom or the like, and n 4 represents an integer from 1 to 6; n 1 represents an integer from 0 to 4; and n 2 represents an integer from 1 to 4, provided that the case where n 1 is 0 and n 2 is 1 is excluded, and a composition which contains the cationic lipid and a nucleic acid, or the like.

First claim

1 . A cationic lipid represented by the formula (I):

wherein R 1 and R 2 are, the same or different, linear or branched alkyl, alkenyl, or alkynyl having 8 to 24 carbon atoms, C7-C20 alkyloxyC1-C3 alkyl, or C7-C20 alkynyloxyC1-C3 alkyl;
R 3 is a hydrogen atom, alkyl having 1 to 3 carbon atoms, the formula (A):

wherein R 4 and R 5 are, the same or different, a hydrogen atom or alkyl having 1 to 3 carbon atoms, or R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a nitrogen-containing heterocycle having 2 to 6 carbon atoms, and n 3 is an integer from 2 to 6, or

the formula (B):

wherein R 6 and R 7 are, the same or different, a hydrogen atom or alkyl having 1 to 3 carbon atoms, or R 6 and R 7 , together with the nitrogen atom to which they are attached, may form a nitrogen-containing heterocycle having 2 to 6 carbon atoms, and n 4 is an integer from 1 to 6;
n 1 is an integer from 0 to 4; and n 2 is an integer from 1 to 4, provided that the case where n 1 is 0 and n 2 is 1 is excluded.

2 . The cationic lipid according to claim 1 , wherein R 1 and R 2 are, the same or different, selected from the group consisting of tetradecyl, hexadecyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-icos-11-enyl, (11Z,14Z)-icosa-11,14-dienyl, and (Z)-docos-13-enyl.

3 . The cationic lipid according to claim 1 , wherein R 1 and R 2 are, the same or different, selected from the group consisting of (Z)-hexadec-9-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, and (11Z,14Z)-icosa-11,14-dienyl.

4 . The cationic lipid according to claim 1 , wherein R 3 is alkyl having 1 to 3 carbon atoms or the formula (A).

5 . The cationic lipid according to claim 1 , wherein R 1 and R 2 are the same.

6 . The cationic lipid according to claim 1 , wherein n 1 is 1, and n 2 is an integer from 1 to 3.

7 . The cationic lipid according to claim 1 , wherein both of n 1 and n 2 are 1.

8 . A cationic lipid represented by the formula (I″):

wherein R 1′ and R 2′ are, the same or different, linear or branched alkyl, alkenyl, or alkynyl having 8 to 24 carbon atoms, C7-C20 alkyloxyC1-C3 alkyl, C7-C20 alkenyloxyC1-C3 alkyl, or C7-C20 alkynyloxyC1-C3 alkyl;
R 3′ is a hydrogen atom, alkyl having 1 to 3 carbon atoms, hydroxyC2-C4 alkyl, C1-C3 dialkylamino-C2-C4 alkyl, the formula (A):

wherein R 4 and R 5 are, the same or different, a hydrogen atom or alkyl having 1 to 3 carbon atoms, or R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a nitrogen-containing heterocycle having 2 to 6 carbon atoms, and n 3 is an integer from 2 to 6, or

the formula (B):

wherein R 6 and R 7 are, the same or different, a hydrogen atom or alkyl having 1 to 3 carbon atoms, or R 6 and R 7 , together with the nitrogen atom to which they are attached, may form a nitrogen-containing heterocycle having 2 to 6 carbon atoms, and n 4 is an integer from 1 to 6;
n t is an integer from 0 to 4; n 2 is an integer from 1 to 4, provided that the case where n 1 is 0 and n 2 is 1 is excluded;
Z 1 is, independently for each carbon atom bonded thereto, a hydrogen atom or alkyl having 1 to 3 carbon atoms; and
Z 2 is, independently for each carbon atom bonded thereto, a hydrogen atom or alkyl having 1 to 3 carbon atoms.

9 . The cationic lipid according to claim 8 , wherein R 1′ and R 2′ are, the same or different, selected from the group consisting of tetradecyl, hexadecyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-icos-11-enyl, (11Z,14Z)-icosa-11,14-dienyl, and (Z)-docos-13-enyl.

10 . The cationic lipid according to claim 8 , wherein R 1′ and R 2′ are, the same or different, selected from the group consisting of (Z)-hexadec-9-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, and (11Z,14Z)-icosa-11,14-dienyl.

11 . The cationic lipid according to claim 8 , wherein R 3′ is alkyl having 1 to 3 carbon atoms or the formula (A).

12 . The cationic lipid according to claim 8 , wherein R 1′ and R 2 ′ are the same.

13 . The cationic lipid according to claim 8 , wherein n 1 is 1, and n 2 is an integer from 1 to 3.

14 . The cationic lipid according to claim 8 , wherein both of n 1 and n 2 are 1.

15 . A composition comprising the cationic lipid according to claim 8 and a nucleic acid.

16 . The composition according to claim 15 , wherein the cationic lipid and the nucleic acid form a complex, or the cationic lipid combined with a neutral lipid and/or a polymer and the nucleic acid form a complex.

17 . The composition according to claim 15 , wherein the cationic lipid and the nucleic acid form a complex, or the cationic lipid combined with a neutral lipid and/or a polymer and the nucleic acid form a complex, and the composition contains a lipid membrane with which the complex is enclosed.

18 . The composition according to claim 15 , wherein the nucleic acid is a nucleic acid having a silencing effect on a target gene through the use of RNA interference (RNAi).

19 . The composition according to claim 18 , wherein the target gene is a gene expressed in the liver, the lung, the kidney, or the spleen.

20 . A method for introducing the nucleic acid into a cell using a composition according to claim 15 .

21 . The method according to claim 20 , wherein the cell is a cell that resides in the liver, the lung, the kidney, or the spleen of a mammal.

22 . The method according to claim 20 , wherein the method for introduction into a cell is a method for introduction into a cell by the intravenous administration of the composition.

23 . A method for treating a disease related to the liver, the lung, the kidney, or the spleen, comprising the step of administering a composition according to claim 19 to a mammal.

24 . The method according to claim 23 , wherein the administration method is intravenous administration.

25 . A medicament for use in the treatment of a disease, comprising a composition according to claim 18 .

26 . The medicament according to claim 25 , wherein the medicament is for intravenous administration.

27 . A therapeutic agent for a disease related to the liver, the lung, the kidney, or the spleen, comprising a composition according to claim 19 .

28 . The therapeutic agent for a disease related to the liver, the lung, the kidney, or the spleen according to claim 27 , wherein the

Assignees

• Kyowa Hakko Kirin Co Ltd

Inventors

• Hosoe Shintaro
• Naoi Tomoyuki

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title